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Volume 17
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Article

Folic Acid and Methyltetrahydrofolate Supplementation in the Mthfr677C>T Mouse Model with Hepatic Steatosis

by
Karen E. Christensen
1,2,
Marie-Lou Faquette
1,2,
Daniel Leclerc
1,2,
Vafa Keser
1,2,
Yan Luan
1,2,
Jeanna L. Bennett-Firmin
3,
Olga V. Malysheva
4,
Alaina M. Reagan
5,
Gareth R. Howell
5,
Marie A. Caudill
4,
Teodoro Bottiglieri
3 and
Rima Rozen
1,2,*
1
Departments of Human Genetics and Pediatrics, McGill University, Montreal, QC H3A 0C7, Canada
2
The Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada
3
Center of Metabolomics, Institute of Metabolic Disease, Baylor Scott and White Research Institute, Dallas, TX 75204, USA
4
Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853, USA
5
The Jackson Laboratory, Bar Harbor, ME 04609, USA
*
Author to whom correspondence should be addressed.
Nutrients 2025, 17(1), 82; https://doi.org/10.3390/nu17010082
Submission received: 19 November 2024 / Revised: 17 December 2024 / Accepted: 25 December 2024 / Published: 28 December 2024
(This article belongs to the Section Micronutrients and Human Health)
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Abstract

Background/Objectives: The MTHFR677C>T gene variant results in a thermolabile MTHFR enzyme associated with elevated plasma homocysteine in TT individuals. Health risks associated with the TT genotype may be modified by dietary and supplemental folate intake. Supplementation with methyltetrahydrofolate (methylTHF) may be preferable to folic acid because it is the MTHFR product, and does not require reduction by DHFR to enter one-carbon folate metabolism. In the Mthfr677C>T mouse model for this variant, female 677TT (TT) mice have an increased incidence of hepatic steatosis. The objective of this study was to compare the effects of methylTHF and folic acid supplementation on hepatic steatosis and one-carbon metabolism in this model. Methods: Male and female C57BL/6J 677CC (CC) and TT mice were fed control (CD), 5xmethylTHF-supplemented (MFSD), or 5xfolic-acid-supplemented (FASD) diets for 4 months. Liver sections were assessed for steatosis by Oil Red O staining. One-carbon metabolites were measured in the liver and plasma. MTHFR protein expression was evaluated in the liver. Results: MFSD had no significant effect on plasma homocysteine, liver SAM/SAH ratios, or hepatic steatosis in males or females as compared to CD. MTHFR protein increased in MFSD TT female liver, but remained <50% of the CC. FASD had no effect on plasma homocysteine but it decreased the liver MTHFR protein and SAM/SAH ratios, and increased hepatic steatosis in CC females. Conclusions: MethylTHF and folic acid supplementation had limited benefits for TT mice, while folic acid supplementation had negative effects on CC females. Further investigation is required to determine if these effects are relevant in humans.
Keywords: folic acid; methyltetrahydrofolate; supplementation; MTHFR; hepatic steatosis; mouse model folic acid; methyltetrahydrofolate; supplementation; MTHFR; hepatic steatosis; mouse model
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MDPI and ACS Style

Christensen, K.E.; Faquette, M.-L.; Leclerc, D.; Keser, V.; Luan, Y.; Bennett-Firmin, J.L.; Malysheva, O.V.; Reagan, A.M.; Howell, G.R.; Caudill, M.A.; et al. Folic Acid and Methyltetrahydrofolate Supplementation in the Mthfr677C>T Mouse Model with Hepatic Steatosis. Nutrients 2025, 17, 82. https://doi.org/10.3390/nu17010082

AMA Style

Christensen KE, Faquette M-L, Leclerc D, Keser V, Luan Y, Bennett-Firmin JL, Malysheva OV, Reagan AM, Howell GR, Caudill MA, et al. Folic Acid and Methyltetrahydrofolate Supplementation in the Mthfr677C>T Mouse Model with Hepatic Steatosis. Nutrients. 2025; 17(1):82. https://doi.org/10.3390/nu17010082

Chicago/Turabian Style

Christensen, Karen E., Marie-Lou Faquette, Daniel Leclerc, Vafa Keser, Yan Luan, Jeanna L. Bennett-Firmin, Olga V. Malysheva, Alaina M. Reagan, Gareth R. Howell, Marie A. Caudill, and et al. 2025. "Folic Acid and Methyltetrahydrofolate Supplementation in the Mthfr677C>T Mouse Model with Hepatic Steatosis" Nutrients 17, no. 1: 82. https://doi.org/10.3390/nu17010082

APA Style

Christensen, K. E., Faquette, M.-L., Leclerc, D., Keser, V., Luan, Y., Bennett-Firmin, J. L., Malysheva, O. V., Reagan, A. M., Howell, G. R., Caudill, M. A., Bottiglieri, T., & Rozen, R. (2025). Folic Acid and Methyltetrahydrofolate Supplementation in the Mthfr677C>T Mouse Model with Hepatic Steatosis. Nutrients, 17(1), 82. https://doi.org/10.3390/nu17010082

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